Tyrosine kinase inhibitors

ABSTRACT

The present invention relates to 5H-benzo[4,5]cyclohepta[1,2-b]pyridine derivatives, that are useful for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the receptor tyrosine kinase MET. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

BACKGROUND OF THE INVENTION

This invention relates to 5H-benzo[4,5]cyclohepta[1,2-b]pyridinecompounds that are inhibitors of tyrosine kinases, in particular thereceptor tyrosine kinase MET, and are useful in the treatment ofcellular proliferative diseases, for example cancer, hyperplasias,restenosis, cardiac hypertrophy, immune disorders and inflammation.

Studies on signal transduction pathways have generated various promisingmolecular targets for therapeutic inhibition in cancer therapy. Receptortyrosine kinases (RTK) represent an important class of such therapeutictargets. Recently, members of the MET proto-oncogene family, a subfamilyof receptor tyrosine kinases, have drawn special attention to theassociation between invasion and metastasis. The MET family, includingMET (also referred to as c-Met) and RON receptors, can function asoncogenes like most tyrosine kinases. MET has been shown to beoverexpressed and/or mutated in a variety of malignancies. A number ofMET activating mutations, many of which are located in the tyrosinekinase domain, have been detected in various solid tumors and have beenimplicated in invasion and metastasis of tumor cells.

The c-Met proto-oncogene encodes the MET receptor tyrosine kinase. TheMET receptor is an approximately 190 kDa glycosylated dimeric complexcomposed of a 50 kDa alpha chain disulfide-linked to a 145 kDa betachain. The alpha chain is found extracellularly while the beta chaincontains extracellular, transmembrane and cytosolic domains. MET issynthesized as a precursor and is proteolytically cleaved to yieldmature alpha and beta subunits. It displays structural similarities tosemaphoring and plexins, a ligand-receptor family that is involved incell-cell interaction.

The natural ligand for MET is hepatocyte growth factor (HGF), adisulfide linked heterodimeric member of the scatter factor family thatis produced predominantly by mesenchymal cells and acts primarily onMET-expressing epithelial and endothelial cells in an endocrine and/orparaendocrine fashion. HGF has some homology to plasminogen.

It is known that stimulation of MET via hepatocyte growth factor (alsoknown as scatter factor, HGF/SF) results in a plethora of biological andbiochemical effects in the cell. Activation of c-Met signaling can leadto a wide array of cellular responses including proliferation, survival,angiogenesis, wound healing, tissue regeneration, scattering, motility,invasion and branching morphogenesis. HGF/MET signaling also plays amajor role in the invasive growth that is found in most tissues,including cartilage, bone, blood vessels, and neurons.

Various c-Met mutations have been well described in multiple solidtumors and some hematologic malignancies. The prototypic c-Met mutationexamples are seen in hereditary and sporadic human papillary renalcarcinoma (Schmidt, L. et al., Nat. Tenet. 1997, 16, 68-73; Jeffers, M.et al., Proc. Nat. Acad. Sci. 1997, 94, 11445-11500). Other reportedexamples of c-Met mutations include ovarian cancer, childhoodhepatocellular carcinoma, metastatic head and neck squamous cellcarcinomas and gastric cancers. HGF/MET has been shown to inhibitanoikis, suspension-induced programmed cell death (apoptosis), in headand neck squamous cell carcinoma cells.

MET signaling is implicated in various cancers, especially renal. Thenexus between MET and colorectal cancer has also been established.Analysis of c-Met expression during colorectal cancer progression showedthat 50% of the carcinoma specimens analyzed expressed 5-50-fold higherlevels of MET mRNA transcripts and protein versus the adjacent normalcolonic mucosa. In addition, when compared to the primary tumor, 70% ofcolorectal cancer liver metastasis showed MET overexpression.

MET is also implicated in glioblastoma. High-grade malignant gliomas arethe most common cancers of the central nervous system. Despite treatmentwith surgical resection, radiation therapy, and chemotherapy, the meanoverall survival is <1.5 years, and few patients survive for >3 years.Human malignant gliomas frequently express both HGF and MET, which canestablish an autocrine loop of biological significance. Glioma METexpression correlates with glioma grade, and an analysis of human tumorspecimens showed that malignant gliomas have a 7-fold higher HGF contentthan low-grade gliomas. Multiple studies have demonstrated that humangliomas frequently co-express HGF and MET and that high levels ofexpression are associated with malignant progression. It was furthershown that HGF-MET is able to activate Akt and protect glioma cell linesfrom apoptotic death, both in vitro and in vivo.

RON shares a similar structure, biochemical features, and biologicalproperties with MET. Studies have shown RON overexpression in asignificant fraction of breast carcinomas and colorectaladenocarcinomas, but not in normal breast epithelia or benign lesions.Cross-linking experiments have shown that RON and MET form anon-covalent complex on the cell surface and cooperate in intracellularsignaling. RON and MET genes are significantly co-expressed in ovariancancer cell motility and invasiveness. This suggests that co-expressionof these two related receptors might confer a selective advantage toovarian carcinoma cells during either tumor onset or progression.

A number of reviews on MET and its function as an oncogene have recentlybeen published: Cancer and Metastasis Review 22:309-325 (2003); NatureReviews/Molecular Cell Biology 4:915-925 (2003); Nature Reviews/Cancer2:289-300 (2002).

Since dysregulation of the HGF/MET signaling has been implicated as afactor in tumorgenesis and disease progression in many tumors, differentstrategies for therapeutic inhibition of this important RTK moleculeshould be investigated. Specific small molecule inhibitors againstHGF/MET signaling and against RON/MET signaling have importanttherapeutic value for the treatment of cancers in which Met activitycontributes to the invasive/metastatic phenotype.

SUMMARY OF THE INVENTION

The present invention relates to 5H-benzo[4,5]cyclohepta[1,2-b]pyridinederivatives, that are useful for treating cellular proliferativediseases, for treating disorders associated with MET activity, and forinhibiting the receptor tyrosine kinase MET. The instant compoundsexhibit reduced time dependent inhibition of the cytochrome P450metabolizing enzymes, especially time dependent inhibition of CYP3A4.The compounds of the invention may be illustrated by the Formula I:

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of tyrosinekinses, in particular the receptor tyrosine kinase MET, and areillustrated by a compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereina is independently 0 or 1;b is independently 0 or 1;m is independently 0, 1, or 2;

R¹ is selected from hydrogen, OH, —O—C₁₋₆alkyl, —O-aryl,—O-heterocyclyl, SH, —S—C₁₋₆alkyl, —S-aryl, —S-heterocyclyl, aryl,heterocyclyl and NR⁸R⁹; said alkyl, aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁶;

R² and R³ are independently selected from: hydrogen, halo,(C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, (C═O)_(a)O_(b)heterocyclyl, O_(b)C₁-C₆ perfluoroalkyl, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl,

said alkyl, aryl, heterocyclyl, and cycloalkyl optionally substitutedwith one, two or three substituents selected from R⁷;

R⁴ and R⁵ are indepedntly selected from hydrogen, C₁₋₆alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, aryl, heterocyclyl, OH, —O—C₁₋₆alkyl,(C₁-C₃)perfluoroalkyl, each alkyl, alkenyl, alkynyl, heterocyclyl andaryl optionally substituted with one to three substituents, eachsubstituent independently selected from R⁶;

R⁶ independently is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, halo,CN, OH, O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a),S(O)₂NR⁸R⁹, OS(═O)R^(a), oxo, CHO, (N═O)R⁸R⁹, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁷;

R⁷ is independently selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo, CN, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a),(C₀-C₆)alkylene-CO₂R^(a), C(O)H, (C₀-C₆)alkylene-CO₂H, C(O)N(R^(b))₂,S(O)_(m)R^(a), and S(O)₂NR⁸R⁹;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with one, two or three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂;

R⁸ and R⁹ are independently selected from: H, (C═O)O_(b)C₁-C₁₀ alkyl,(C═O)O_(b)C₃-C₈ cycloalkyl, (C═O)O_(b)aryl, (C═O)O_(b)heterocyclyl,C₁-C₁₀ alkyl, aryl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₈cycloalkyl, SO₂R^(a), and (C═O)NR^(b) ₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl isoptionally substituted with one, two or three substituents selected fromR⁶, or

R⁸ and R⁹ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁷;

R^(a) is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; and

R^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

Another embodiment of the present invention is illustrated by a compoundof Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereina is independently 0 or 1;b is independently 0 or 1;m is independently 0, 1, or 2;

R¹ is selected from hydrogen, OH, —O—C₁₋₆alkyl, —O-aryl,—O-heterocyclyl, SH, —S—C₁₋₆alkyl, —S-aryl, —S-heterocyclyl, aryl,heterocyclyl and NR⁸R⁹; said alkyl, aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁶;

R⁴ and R⁵ are indepedntly selected from hydrogen, C₁₋₆alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, aryl, heterocyclyl, OH, —O—C₁₋₆alkyl,(C₁-C₃)perfluoroalkyl, each alkyl, alkenyl, alkynyl, heterocyclyl andaryl optionally substituted with one to three substituents, eachsubstituent independently selected from R⁶;

R⁶ independently is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, (C═O)_(a)O_(b)heterocyclyl, CO₂H, halo,CN, OH, O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a),S(O)₂NR⁸R⁹, OS(═O)R^(a), oxo, CHO, (N═O)R⁸R⁹, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁷;

R⁷ is independently selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo, CN, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a),(C₀-C₆)alkylene-CO₂R^(a), C(O)H, (C₀-C₆)alkylene-CO₂H, C(O)N(R^(b))₂,S(O)_(m)R^(a), and S(O)₂NR⁸R⁹;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with one, two or three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂;

R⁸ and R⁹ are independently selected from: H, (C═O)O_(b)C₁-C₁₀C alkyl,(C═O)O_(b)C₃-C₈ cycloalkyl, (C═O)O_(b)aryl, (C═O)O_(b)heterocyclyl,C₁-C₁₀ alkyl, aryl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₈cycloalkyl, SO₂R^(a), and (C═O)NR^(b) ₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl isoptionally substituted with one, two or three substituents selected fromR⁶, or

R⁸ and R⁹ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁷;

R^(a) is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; and

R^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

A further embodiment of the present invention is illustrated by acompound of Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereina is independently 0 or 1;b is independently 0 or 1;m is independently 0, 1, or 2;

R¹ is selected from OH, —O—C₁₋₆alkyl, —O-aryl, —O-heterocyclyl, aryl,heterocyclyl and NR⁸R⁹; said alkyl, aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁶;

R⁴ is selected from hydrogen, C₁₋₆alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,aryl, heterocyclyl, OH, —O—C₁₋₆alkyl, (C₁-C₃)perfluoroalkyl, each alkyl,alkenyl, alkynyl, heterocyclyl and aryl optionally substituted with oneto three substituents, each substituent independently selected from R⁶;

R⁶ independently is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, (C═O)_(a)O_(b)heterocyclyl, CO₂H, halo,CN, OH, O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a),S(O)₂NR⁸R⁹, OS(═O)R^(a), oxo, CHO, (N═O)R⁸R⁹, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁷;

R^(6a) is selected from: C₁-C₁₀ alkyl, aryl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, heterocyclyl, C₃-C₉ cycloalkyl, C₁-C₆ perfluoroalkyl,(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a) or S(O)₂NR⁸R⁹, said alkyl, aryl, alkenyl,alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one,two or three substituents selected from R⁹;

R⁷ is independently selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo, CN, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a),(C₀-C₆)alkylene-CO₂R^(a), C(O)H, (C₀-C₆)alkylene-CO₂H, C(O)N(R^(b))₂,S(O)_(m)R^(a), and S(O)₂NR⁸R⁹;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with one, two or three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂;

R⁸ and R⁹ are independently selected from: H, (C═O)O_(b)C₁-C₁₀ alkyl,(C═O)O_(b)C₃-C₈ cycloalkyl, (C═O)O_(b)aryl, (C═O)O_(b)heterocyclyl,C₁-C₁₀ alkyl, aryl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₉cycloalkyl, SO₂R^(a), and (C═O)NR^(b) ₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl isoptionally substituted with one, two or three substituents selected fromR⁶, or

R⁸ and R⁹ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁷;

R^(a) is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; and

R^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

Specific examples of the compounds of the instant invention include:

-   N,N-Dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-benzyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(1,4-dioxan-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1-phenylethyl)methanesulfonamide;-   N-(4-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(2-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-methoxybenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(4-methoxybenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(4-fluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(2,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(2-phenylethyl)methanesulfonamide;-   N-(cyclohexylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-isobutyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-methylbutyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(1-methyl-1H-imidazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-furylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-propylmethanesulfonamide;-   N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-3-ylmethyl)methane-sulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-methylpyridin-2-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-4-ylmethyl)methanesulfonamide;-   1,1-Difluoro-N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-Fluoro-N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-3-ylmethanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide;-   N-[(5-methylpyrazin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(5-methylisoxazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-1,2,4-triazol-5-ylmethyl)methanesulfonamide;-   N-(1H-benzimidazol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(1H-imidazol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(1H-indol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-5-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-methylpyridin-4-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(3-thienylmethyl)methanesulfonamide;-   N-(imidazo[1,2-a]pyridin-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(3-methylisoxazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(imidazo[2,1-b][1,3]thiazol-6-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-phenylisoxazol-5-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(4-methyl-1,3-thiazol-2-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-pyridin-2-ylisoxazol-5-yl)methyl]methanesulfonamide;-   N-[4-(1H-imidazol-4-yl)benzyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-{[6-(trifluoromethyl)-pyridin-2-yl]methyl}-methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(2-morpholin-4-yl-2-oxoethyl)methanesulfonamide;-   N˜2˜-({[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl}sulfonyl)glycinamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-{[2-(2-thienyl)-1,3-thiazol-4-yl]methyl}methanesulfonamide;-   N-[(2-benzyl-1,3-thiazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-pyrazol-3-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,2,3-thiadiazol-4-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridazin-4-ylmethyl)methanesulfonamide;-   N-[(1-methyl-1H-pyrazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-ylmethyl)methanesulfonamide;-   N-[(1-methyl-1H-imidazol-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-oxazol-2-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-phenyl-1H-pyrazol-4-yl)methyl]methanesulfonamide;-   N-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-pyrazol-5-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-1,2,3-triazol-4-ylmethyl)methanesulfonamide;-   N-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrimidin-2-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrimidin-4-ylmethyl)methanesulfonamide;-   N-[(4,6-dimethylpyrimidin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(3,5-difluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-4-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrazin-2-ylmethyl)methanesulfonamide;-   N-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-oxazol-4-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrimidin-5-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-phenyl-1,3-thiazol-5-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(6-methylpyridin-2-yl)methyl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1-pyridin-2-ylethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridazin-3-ylmethyl)methanesulfonamide;-   N-[(5-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(3-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(6-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(6-bromopyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(5-chloropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(6-chloropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-ethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-4-ylmethane-sulfonamide;-   N-(2-hydroxyethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-2-ylmethanesulfonamide;-   N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)ethanesulfonamide;-   N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylethanesulfonamide;-   1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;-   1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;    and-   1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(1-oxidopyridin-2-yl)methyl]methanesulfonamide    or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention. In addition, the compounds disclosedherein may exist as tautomers and both tautomeric forms are intended tobe encompassed by the scope of the invention, even though only onetautomeric structure is depicted.

When any variable (e.g. R⁷, R⁸, R^(b), etc.) occurs more than one timein any constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases another embodiment will havefrom zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on. Inan embodiment of the invention the term “cycloalkyl” includes the groupsdescribed immediately above and further includes monocyclic unsaturatedaliphatic hydrocarbon groups. For example, “cycloalkyl” as defined inthis embodiment includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl,cyclobutenyl and so on.

The term “alkylene” means a hydrocarbon diradical group having thespecified number of carbon atoms. For example, “alkylene” includes—CH₂—, —CH₂CH₂— and the like.

When used in the phrases “C₁-C₆ aralkyl” and “C₁-C₆ heteroaralkyl” theterm “C₁-C₆” refers to the alkyl portion of the moiety and does notdescribe the number of atoms in the aryl and heteroaryl portion of themoiety.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3 to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. For the purposes of this invention, theterm “heterocyclic” is also considered to be synonymous with the terms“heterocycle” and “heterocyclyl” and is understood as also having thedefinitions set forth herein.

“Heterocyclyl” therefore includes the above mentioned heteroaryls, aswell as dihydro and tetrathydro analogs thereof. Further examples of“heterocyclyl” include, but are not limited to the following:azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In an embodiment, the term “heterocycle” or “heterocyclyl” as usedherein is intended to mean a 5- to 10-membered aromatic or nonaromaticheterocycle containing from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S, and includes bicyclic groups. “Heterocyclyl”in this embodiment therefore includes the above mentioned heteroaryls,as well as dihydro and tetrathydro analogs thereof. Further examples of“heterocyclyl” include, but are not limited to the following:benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In another embodiment, heterocycle is selected from 2-azepinone,benzimidazolyl, 2-diazapinone, imidazolyl, 2-imidazolidinone, indolyl,isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl,pyrrolidinyl, 2-piperidinone, 2-pyrimidinone, 2-pyrollidinone,quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo.

The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl substituents may be substituted or unsubstituted, unlessspecifically defined otherwise. For example, a (C₁-C₆)alkyl may besubstituted with one, two or three substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl,piperidinyl, and so on. In this case, if one substituent is oxo and theother is OH, the following are included in the definition:

—C═O)CH₂CH(OH)CH₃, —(C═O)OH, —CH₂(OH)CH₂CH(O), and so on.

The moiety formed when, in the definition of two R⁸ or two R⁹ on thesame carbon atom are combined to form —(CH₂)_(u)— is illustrated by thefollowing:

In addition, such cyclic moieties may optionally include one or twoheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to:

In certain instances, R¹⁰ and R¹¹ are defined such that they can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one or more substituents selected from R⁸.Examples of the heterocycles that can thus be formed include, but arenot limited to the following, keeping in mind that the heterocycle isoptionally substituted with one or more (and in another embodiment, one,two or three) substituents chosen from R⁸:

In an embodiment of the compound of the Formula I, R¹ is selected fromaryl, heterocyclyl and NR⁸R⁹; said aryl and heterocyclyl groupoptionally substituted with one to three substituents, each substituentindependently selected from R⁶.

In an embodiment of the compound of the Formula I, R² and R³ areindependently selected from: hydrogen, halo and C₁-C₁₀ alkyl.

In an embodiment of the compound of the Formula I, R⁴ is selected fromhydrogen, and C₁₋₆alkyl, each alkyl optionally substituted with one tothree substituents, each substituent independently selected from R⁶; andR⁵ is selected from hydrogen, C₁₋₁₆alkyl, aryl, heterocyclyl,(C₁-C₃)perfluoroalkyl, each alkyl, heterocyclyl and aryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶.

In another embodiment of the compounds of Formula I, R⁴ is selected fromaryl, heterocyclyl and NR⁸R⁹; said aryl and heterocyclyl groupoptionally substituted with one to three substituents, each substituentindependently selected from R⁶;

R² and R³ are independently selected from: hydrogen, halo and C₁-C₁₀alkyl;R⁴ is selected from hydrogen, and C₁₋₁₆alkyl, each alkyl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;R⁵ is selected from hydrogen, C₁₋₆alkyl, aryl, heterocyclyl,(C₁-C₃)perfluoroalkyl, each alkyl, heterocyclyl and aryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;R⁶ independently is:

-   -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀        alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)        CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)        O_(a)(C═O)_(b)NR⁸R⁹, 12) S(O)_(m)R^(a), 13) S(O)₂NR⁸R⁹, 14)        OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R⁸R⁹, 18)        (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one, two or three substituents        selected from R⁷.

In a further embodiment of the compounds of Formula I, R¹ is1-methylpyrazol-4-yl;

R² and R³ are: hydrogen;

R⁴ is selected from hydrogen, and C₁₋₆alkyl, each alkyl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R⁵ is selected from hydrogen, C₁₋₆alkyl, aryl, heterocyclyl,(C₁-C₃)perfluoroalkyl, each alkyl, heterocyclyl and aryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R⁶ independently is:

-   -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀        alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)        CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)        O_(a)(C═O)_(b)NR⁸R⁹, 12) S(O)_(m)R^(a), 13) S(O)₂NR⁸R⁹, 14)        OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R⁸R⁹, 18)        (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one, two or three substituents        selected from R⁷.

In an embodiment of the compound of the Formula II, R¹ is selected fromaryl, heterocyclyl and NR⁸R⁹; said aryl and heterocyclyl groupoptionally substituted with one to three substituents, each substituentindependently selected from R⁶.

In an embodiment of the compound of the Formula II, R⁴ is selected fromhydrogen, and C₁₋₁₆alkyl, each alkyl optionally substituted with one tothree substituents, each substituent independently selected from R⁶; andR⁵ is selected from hydrogen, C₁₋₆alkyl, aryl, heterocyclyl, and(C₁-C₃)perfluoroalkyl, each alkyl, heterocyclyl and aryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶.

In another embodiment of the compounds of Formula II, R¹ is selectedfrom aryl, heterocyclyl and NR⁸R⁹; said aryl and heterocyclyl groupoptionally substituted with one to three substituents, each substituentindependently selected from R⁶;

R⁴ is selected from hydrogen, and C₁₋₁₆alkyl, each alkyl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R⁵ is selected from hydrogen, C₁₋₁₆alkyl, aryl, heterocyclyl,(C₁-C₃)perfluoroalkyl, each alkyl, heterocyclyl and aryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R⁶ independently is:

-   -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀        alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)        CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)        O_(a)(C═O)_(b)NR⁸R⁹, 12) S(O)_(m)R^(a), 13) S(O)₂NR⁸R⁹, 14)        OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R⁸R⁹, 18)        (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one, two or three substituents        selected from R⁷.

In a further embodiment of the compounds of Formula II, R¹ is1-methylpyrazol-4-yl;

R⁴ is selected from hydrogen, and C₁₋₆alkyl, each alkyl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R⁵ is selected from hydrogen, C₁₋₆alkyl, aryl, heterocyclyl,(C₁-C₃)perfluoroalkyl, each alkyl, heterocyclyl and aryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R⁶ independently is:

-   -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀        alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)        CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)        O_(a)(C═O)_(b)NR⁸R⁹, 12) S(O)_(m)R^(a), 13) S(O)₂NR⁸R⁹, 14)        OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R⁸R⁹, 18)        (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one, two or three substituents        selected from R⁷.

In an embodiment of the compound of the Formula III, R¹ is selected fromaryl, heterocyclyl and NR⁸R⁹; said aryl and heterocyclyl groupoptionally substituted with one to three substituents, each substituentindependently selected from R⁶.

In an embodiment of the compound of the Formula III, R⁴ is selected fromhydrogen, and C₁₋₆alkyl, each alkyl optionally substituted with one tothree substituents, each substituent independently selected from R⁶

In an embodiment of the compound of the Formula III, R^(6a) is selectedfrom aryl and heteroaryl, each aryl and heteroaryl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶.

In another embodiment of the compounds of Formula III, R¹ is selectedfrom aryl, heterocyclyl and NR⁸R⁹; said aryl and heterocyclyl groupoptionally substituted with one to three substituents, each substituentindependently selected from R⁶;

R⁴ is selected from hydrogen, and C₁₋₆alkyl, each alkyl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R^(6a) is selected from aryl and heteroaryl, each aryl and heteroaryloptionally substituted with one to three substituents, each substituentindependently selected from R⁶;

R⁶ independently is:

-   -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀        alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)        CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)        O_(a)(C═O)_(b)NR⁸R⁹, 12) S(O)_(m)R^(a), 13) S(O)₂NR⁸R⁹, 14)        OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R⁸R⁹, 18)        (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one, two or three substituents        selected from R⁷.

In a further embodiment of the compounds of Formula III, R¹ is1-methylpyrazol-4-yl;

R⁴ is selected from hydrogen, and C₁₋₆alkyl, each alkyl optionallysubstituted with one to three substituents, each substituentindependently selected from R⁶;

R^(6a) is selected from aryl and heteroaryl, each aryl and heteroaryloptionally substituted with one to three substituents, each substituentindependently selected from R⁶;

R⁶ independently is:

-   -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀        alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b)heterocyclyl, 6)        CO₂H, 7) halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)        O_(a)(C═O)_(b)NR⁸R⁹, 12) S(O)_(m)R^(a), 13) S(O)₂NR⁸R⁹, 14)        OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R⁸R⁹, 18)        (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one, two or three substituents        selected from R⁷.

Included in the instant invention is the free form of compounds ofFormulae I, II and III, as well as the pharmaceutically acceptable saltsand stereoisomers thereof. Some of the specific compounds exemplifiedherein are the protonated salts of amine compounds. The term “free form”refers to the amine compounds in non-salt form. The encompassedpharmaceutically acceptable salts not only include the salts exemplifiedfor the specific compounds described herein, but also all the typicalpharmaceutically acceptable salts of the free form of compounds ofFormula I. The free form of the specific salt compounds described may beisolated using techniques known in the art. For example, the free formmay be regenerated by treating the salt with a suitable dilute aqueousbase solution such as dilute aqueous NaOH, potassium carbonate, ammoniaand sodium bicarbonate. The free forms may differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like. When the compound of thepresent invention is acidic, the term “free form” refers to the compoundin its non-salt form, such that the acidic functionality is stillprotonated.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention maypotentially be internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom. An isolatedcompound having internally balance charges, and thus not associated witha intermolecular counterion, may also be considered the “free form” of acompound.

Certain abbreviations, used in the Schemes and Examples, are definedbelow:

APCI Atmospheric pressure chemical ionizationDCM dichloromethane

DMF Dimethylformamide

DMSO Dimethyl sulfoxideEtOAc Ethyl acetateLCMS Liquid chromatographic mass spectrometryMPLC Medium pressure liquid chromatography

NBS N-bromosuccinamide NFSI N-fluorobenzenesulfonamide

TFA Trifluoroacetic acidTFAA Trifluoroacetic anhydride

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. The illustrative schemes below, therefore, arenot limited by the compounds listed or by any particular substituentsemployed for illustrative purposes. Substituent numbering as shown inthe schemes does not necessarily correlate to that used in the claimsand often, for clarity, a single substituent is shown attached to thecompound where multiple substituents are allowed under the definitionsof Formula I hereinabove.

Schemes

As shown in Scheme A, reaction of a suitably substituted2-methylnicotinate A-1 with strong base followed by reaction with asuitably substituted bromobenzaldehyde provides the olefin intermediateA-2. Subequent poplyphiosphonic acid mediated cyclization provides theintermediate/compound of the invention A-3.

Scheme B illustrates the synthesis of key intermediate B-3.

Scheme C illustrates the incorporation of the aminosulfonylmethylsubstituent on the 5H-benzo[4,5]cyclohepta[1,2-b]pyridine ring system.Thus, the methylaminosulfonyl acetate C-2 is reacted with intermediateB-3 to provide the intermediate C-3. Saponification of C-3 providescompound C-4, which can undergo a Suzuki coupling with an appropriatelysubstituted boronic acid or boronic ester to provide the instantcompound C-5.

Scheme D illustrates derivatization of the aminosulfonylmethyl moiety ofC-5. Thus, transamination with a suitably substituted amine providesinstant compound D-1. Difluorination and incorporation of a methyl groupon the methylene spacer (D-2 and D-3 respectively) is also illustrated.

Selective monofluorination of the methylene spacer of the instantcompounds is illustrated in Scheme E.

An alternative synthetic procedure for incorporating the suitablysubstituted aminosulfonyl moiety of the instant compounds is illustratedin Scheme F.

Scheme G illustrates an alternative procedure for forming the tricyclicring system of the instant compounds. Thus a suitably substitutednicotinoyl chloride G-1 is converted to intermediate G-2, which reactswith a suitably substituted boronic acid to provide the benzaldehydeG-3. Intermediate G-3 can then undergo base mediated cyclization toprovide the instant compound G-4.

Utilities

The compounds of the invention are useful to bind to and/or modulate theactivity of a tyrosine kinase, in particular, a receptor tyrosinekinase. In an embodiment, the receptor tyrosine kinase is a member ofthe MET subfamily. In a further embodiment, the MET is human MET,although the activity of receptor tyrosine kinases from other organismsmay also be modulated by the compounds of the present invention. In thiscontext, modulate means either increasing or decreasing kinase activityof MET. In an embodiment, the compounds of the instant invention inhibitthe kinase activity of MET.

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, the kinase activity ofMET may be modulated in a variety of ways; that is, one can affect thephosphorylation/activation of MET either by modulating the initialphosphorylation of the protein or by modulating the autophosphorylationof the other active sites of the protein. Alternatively, the kinaseactivity of MET may be modulated by affecting the binding of a substrateof MET phosphorylation.

The compounds of the invention are used to treat or prevent cellularproliferation diseases. Disease states which can be treated by themethods and compositions provided herein include, but are not limitedto, cancer (further discussed below), autoimmune disease, arthritis,graft rejection, inflammatory bowel disease, proliferation induced aftermedical procedures, including, but not limited to, surgery, angioplasty,and the like. It is appreciated that in some cases the cells may not bein a hyper- or hypoproliferation state (abnormal state) and stillrequire treatment. Thus, in one embodiment, the invention hereinincludes application to cells or individuals which are afflicted or mayeventually become afflicted with any one of these disorders or states.

The compounds, compositions and methods provided herein are particularlydeemed useful for the treatment and prevention of cancer including solidtumors such as skin, breast, brain, cervical carcinomas, testicularcarcinomas, etc. In an embodiment, the instant compounds are useful fortreating cancer. In particular, cancers that may be treated by thecompounds, compositions and methods of the invention include, but arenot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia,), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions. In an embodiment of the invention, cancersthat may be treated by the compounds, compositions and methods of theinvention include, in addition to the cancers listed above: Lung:bronchogenic carcinoma (non-small cell lung); Gastrointestinal: rectal,colorectal and colon; Genitourinary tract: kidney (papillary renal cellcarcinoma); and Skin: head and neck squamous cell carcinoma.

In another embodiment, the compounds of the instant invention are usefulfor treating or preventing cancer selected from: head and neck squamouscell carcinomas, histiocytic lymphoma, lung adenocarcinoma, small celllung cancer, non-small cell lung cancer, pancreatic cancer, papillaryrenal cell carcinoma, liver cancer, gastric cancer, colon cancer,multiple myeloma, glioblastomas and breast carcinoma. In yet anotherembodiment, the compounds of the instant invention are useful fortreating or preventing cancer selected from: histiocytic lymphoma, lungadenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer,gastric cancer, colon cancer, multiple myeloma, glioblastomas and breastcarcinoma. In still another embodiment, the compounds of the instantinvention are useful for treating cancer selected from: histiocyticlymphoma, lung adenocarcinoma, small cell lung cancers, pancreaticcancer, liver cancer, gastric cancer, colon cancer, multiple myeloma,glioblastomas and breast carcinoma.

In another embodiment, the compounds of the instant invention are usefulfor the prevention or modulation of the metastases of cancer cells andcancer. In particular, the compounds of the instant invention are usefulto prevent or modulate the metastases of ovarian cancer, childhoodhepatocellular carcinoma, metastatic head and neck squamous cellcarcinomas, gastric cancers, breast cancer, colorectal cancer, cervicalcancer, lung cancer, nasopharyngeal cancer, pancreatic cancer,glioblastoma and sarcomas.

The compounds of this invention may be administered to mammals,preferably humans, either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropyl-methylcellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type,species, age, weight, sex and the type of cancer being treated; theseverity (i.e., stage) of the cancer to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to treat, for example, to prevent,inhibit (fully or partially) or arrest the progress of the disease.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

In a further example, compounds of the instant invention can beadministered in a total daily dose of up to 1000 mg. Compounds of theinstant invention can be administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), and three times daily(TID). Compounds of the instant invention can be administered at a totaldaily dosage of up to 1000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800mg or 1000 mg, which can be administered in one daily dose or can bedivided into multiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

The instant compounds are also useful in combination with knowntherapeutic agents and anti-cancer agents. For example, instantcompounds are useful in combination with known anti-cancer agents.Combinations of the presently disclosed compounds with other anti-canceror chemotherapeutic agents are within the scope of the invention.Examples of such agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb.15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such anti-cancer agents include, but arenot limited to, the following: estrogen receptor modulators, androgenreceptor modulators, retinoid receptor modulators, cytotoxic/cytostaticagents, antiproliferative agents, prenyl-protein transferase inhibitors,HMG-CoA reductase inhibitors and other angiogenesis inhibitors,inhibitors of cell proliferation and survival signaling, apoptosisinducing agents and agents that interfere with cell cycle checkpoints.The instant compounds are particularly useful when co-administered withradiation therapy.

In an embodiment, the instant compounds are also useful in combinationwith known anti-cancer agents including the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic agents, antiproliferative agents, prenyl-protein transferaseinhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, and other angiogenesis inhibitors.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfantosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa,lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroOxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO03/049,678, WO04/039774, WO03/079973, WO03/099211, WO03/105855,WO03/106417, WO04/037171, WO04/058148, WO04/058700, WO04/126699,WO05/018638, WO05/019206, WO05/019205, WO05/018547, WO05/017190,US2005/0176776. In an embodiment inhibitors of mitotic kinesins include,but are not limited to inhibitors of KSP, inhibitors of MKLP1,inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif14,inhibitors of Mphosph1 and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98, valproic acid andscriptaid. Further reference to other histone deacetylase inhibitors maybe found in the following manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR® see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structuralformulas of these and additional HMG-CoA reductase inhibitors that maybe used in the instant methods are described at page 87 of M. Yalpani,“Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb.1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoAreductase inhibitor as used herein includes all pharmaceuticallyacceptable lactone and open-acid forms (i.e., where the lactone ring isopened to form the free acid) as well as salt and ester forms ofcompounds which have HMG-CoA reductase inhibitory activity, and thereforthe use of such salts, esters, open-acid and lactone forms is includedwithin the scope of this invention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betarnethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in PCT Publication WO03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

“Inhibitors of cell proliferation and survival signaling pathway” referto pharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors ofPI3K (for example LY294002), serine/threonine kinases (including but notlimited to inhibitors of Akt such as described in WO 02/083064, WO02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360,WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/096135, WO2004/096130, WO 2005/100356, WO 2005/100344), inhibitors of Rafkinase(for example BAY-43-9006), inhibitors of MEK (for example CI-1040 andPD-098059) and inhibitors of mTOR (for example Wyeth CCI-779). Suchagents include small molecule inhibitor compounds and antibodyantagonists.

“Apoptosis inducing agents” include activators of TNF receptor familymembers (including the TRAIL receptors).

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat. No.5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S. Pat.No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752, U.S.Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No. 5,698,584,U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991, U.S. Pat.No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No. 5,393,790, U.S.Pat. No. 5,466,823, U.S. Pat. No. 5,633,272, and U.S. Pat. No.5,932,598, all of which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine;or a pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)-phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RP14610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅μ₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₈, α₁β₁,α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382, 2, 3, 9, 10, 11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, imatinib (STI571), CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Opthalmol. Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, G1262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am J Hum Genet 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998; 5(8):1105-13), andinterferon gamma (J Immunol 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In an embodiment, an anti-emesis agentselected from a neurokinin-1 receptor antagonist, a 5HT3 receptorantagonist and a corticosteroid is administered as an adjuvant for thetreatment or prevention of emesis that may result upon administration ofthe instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0443 132, 0482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications, which are incorporatedherein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited to:anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

The compounds of the instant invention may also be administered incombination with γ-secretase inhibitors and/or inhibitors of NOTCHsignaling. Such inhibitors include compounds described in WO 01/90084,WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370,WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137,WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO02/47671 (including LY-450139).

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with PARP inhibitors.

A compound of the instant invention may also be useful for treatingcancer in combination with the following therapeutic agents: abarelix(Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®);Alemtuzumabb (Campath®); alitretinoin (Panreting); allopurinol(Zyloprim®); altretamine (Hexylen®); amifostine (Ethyol®); anastrozole(Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®);azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules(Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®);bortezomib (Velcade®&); busulfan intravenous (Busulfex®); busulfan oral(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®);carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine(Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®);celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®);cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine(Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide(Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukindiftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®);doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®);DROMOSTANOLONE PROPIONATE (DROMOSTANOLONE®); DROMOSTANOLONE PROPIONATE(MASTERONE INJECTION®); Elliott's B Solution (Elliott's B Solution®);epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide,VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®);floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide(Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®,Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®);lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®);megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnextabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C(Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®);nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®);Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxating);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-boundparticles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®);pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin(Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®);porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine(Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim(Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin(Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen(Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®);vincristine (Oncovin®); vinorelbine (Navelbine®); and zoledronate(Zometa®).

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from: an estrogen receptor modulator, an androgen receptormodulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, anantiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, aPPAR-δ agonist, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, an apoptosisinducing agent, a bisphosphonate, an aromatase inhibitor, an siRNAtherapeutic γ-secretase inhibitors, agents that interfere with receptortyrosine kinases (RTKs), an agent that interferes with a cell cyclecheckpoint and any of the therapeutic agents listed above.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter referred to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention. In addition,anti-cancer treatment can be administered during the period ofadministration of a compound of the instant invention but does not needto occur over the entire treatment period of a compound of the instantinvention.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

In an embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of Formula I in combination with radiation therapy and/or incombination with a compound selected from: an estrogen receptormodulator, an androgen receptor modulator, retinoid receptor modulator,a cytotoxic/cytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, anangiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitorof inherent multidrug resistance, an anti-emetic agent, an agent usefulin the treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an inhibitor of cellproliferation and survival signaling, an apoptosis inducing agent, abisphosphonate, an aromatase inhibitor, an siRNA therapeutic and anagent that interferes with a cell cycle checkpoint.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with a COX-2 inhibitor.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of Formula I and a compound selectedfrom: an estrogen receptor modulator, an androgen receptor modulator, aretinoid receptor modulator, a cytotoxic/cytostatic agent, anantiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, aPPAR-δ agonist; an inhibitor of cell proliferation and survivalsignaling, a bisphosphonate, an aromatase inhibitor, an siRNAtherapeutic and an agent that interferes with a cell cycle checkpoint.

Further included within the scope of the invention is a method oftreating or preventing a disease in which angiogenesis is implicated,which is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention. Other inhibitors of MET may also be administered forthis method of treatment. Ocular neovascular diseases, which may resultin certain forms of blindness, are examples of conditions where much ofthe resulting tissue damage can be attributed to aberrant infiltrationof blood vessels in the eye. The undesirable infiltration can betriggered by ischemic retinopathy, such as that resulting from diabeticretinopathy, retinopathy of prematurity, retinal vein occlusions, etc.,or by degenerative diseases, such as the choroidal neovascularizationobserved in age-related macular degeneration. Inhibiting the growth ofblood vessels by administration of the present compounds would thereforeprevent the infiltration of blood vessels and prevent or treat diseaseswhere angiogenesis is implicated, such as ocular diseases like retinalvascularization, diabetic retinopathy, age-related macular degeneration,and the like.

Routes of systemic administration of the compounds of the presentinvention described above may be utilized in the treatment of suchocular neovascular diseases. Other routes of ocular administration mayalso be employed, such as topical, periocular, intravitreal and thelike. Intravitreal implants coated with a drug:polymer matrix may alsobe employed.

Ophthalmic pharmaceutical compositions that are adapted for topicaladministration to the eye may be in the form of solutions, suspensions,ointments, creams or as a solid insert. Ophthalmic formulations of thiscompound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% ofmedicament. For a single dose, from between 0.01 to 5000 ng, preferably0.1 to 500 ng, and especially 1 to 100 ng of the compound can be appliedto the human eye. Formulations useful for intravitreal administrationare similar to saline solutions described previously for intravenousadministration.

These and other aspects of the invention will be apparent from theteachings contained herein.

Assays

The compounds of the instant invention described in the Examples weretested by the assays described below and were found to have METinhibitory activity. Other assays are known in the literature and couldbe readily performed by those of skill in the art (see, for example,U.S. Patent Application Publications US 2005/0075340 A1, Apr. 7, 2005,pages 18-19; and PCT Publication WO 2005/028475, Mar. 31, 2005, pages236-248).

I. In Vitro Kinase Assays

Recombinant GST-tagged cytosolic domains of human c-Met and otherreceptor tyrosine kinases including mouse c-Met, human Ron, KDR, IGFR,EGFR, FGFR, Mer, TrkA and Tie2 are used to determine whether thecompounds of the instant invention modulate the enzymatic activities ofthese kinases.

Soluble recombinant GST-tagged cytosolic domains of c-Met and otherreceptor tyrosine kinases are expressed in a baculovirus system(Pharmingen) according to a protocol recommended by the manufacturer.The c-DNA encoding each cytosolic domain is subcloned into a baculovirusexpression vector (pGcGHLT-A, B or C, Pharmingen) containing an in frame6× histidine tag and a GST tag. The resulting plasmid construct andBaculoGold baculovirus DNA (Pharmingen) are used to co-transfect Sf9 orSf21 insect cells. After confirming expression of GST-tagged kinasefusion, a high titer recombinant baculovirus stock is produced,expression conditions are optimized, and a scaled up expression of ratKDR-GST fusion is performed. The fusion kinase is then purified from theinsect cell lysate by affinity chromatography using glutathione agarose(Pharmingen). The purified protein is dialyzed against 50% glycerol, 2mM DTT, 50 mM Tris-HCl (pH 7.4) and stored at −20° C. The proteinconcentrations of the fusion proteins are determined using CoomassiePlus Protein Assay (Pierce) with BSA as standard.

The kinase activities of c-Met and other kinases are measured using amodified version of the homogeneous time-resolved tyrosine kinase assaydescribed by Park et al. (1999, Anal. Biochem. 269:94-104).

The procedure for determining the potency of a compound to inhibit c-Metkinase comprises the following steps:

-   -   1. Prepare 3-fold serial diluted compound solutions in 100%        dimethyl sulfoxide (DMSO) at 20× of the desired final        concentrations in a 96 well plate.    -   2. Prepare a master reaction mix containing 6.67 mM MgCl₂, 133.3        mM NaCl, 66.7 mM Tris-HCl (pH 7.4), 0.13 mg/ml BSA, 2.67 mM        dithiothreitol, 0.27 nM recombinant c-Met and 666.7 nM        biotinylated synthetic peptide substrate        (biotin-ahx-EQEDEPEGDYFEWLE-CONH₂) (SEQ. ID. NO.: 1).    -   3. In a black assay plate, add 2.5 μl of compound solution (or        DMSO) and 37.5 μl of master reaction mix per well. Initiate the        kinase reaction by adding 10 μl of 0.25 mM MgATP per well. Allow        the reactions to proceed for 80 min at room temperature. The        final conditions for the reaction are 0.2 nM c-Met, 0.5 μM        substrate, 50 μM MgATP, 5 mM MgCl₂, 100 mM NaCl, 2 mM DTT, 0.1        mg/ml BSA, 50 mM Tris (pH 7.4) and 5% DMSO.    -   4. Stop the kinase reaction with 50 μl of Stop/Detection buffer        containing 10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100, 0.126        μg/ml Eu-chelate labeled anti-phosphotyrosine antibody PY20        (cat. # AD0067, PerkinElmer) and 45 μg/ml        Streptavidin-allophycocyanin conjugate (cat. # PJ25S, Prozyme).    -   5. Read HTRF signals on a Victor reader (PerkinElmer) in HTRF        mode after 60 min.    -   6. IC₅₀ is determined by fitting the observed relationship        between compound concentration and HTRF signal with a        4-parameter logistic equation.        Essentially the same procedure was used to determine the potency        of compounds to inhibit mouse c-Met, human Ron, KDR, IGFR, EGFR,        FGFR, Mer, TrkA and Tie2 except that the concentration of enzyme        varied in individual assays (0.2 nM mouse c-Met; 2.5 nM Ron, 8        nM KDR; 0.24 nM IGFR; 0.24 nM EGFR; 0.14 nM FGFR; 16 nM Mer; 8        nM TrkA; 8 nM Tie2).

The compound of the instant invention may be tested in the assay aboveand inhibitory activity may be determined. The compounds 2-4, 3-1 to3-26. 4-1, 4-2, 5-5, 6-1 to 6-76, 7-1 and 8-2 in the Examples weretested in the above assay and found to have an IC₅₀<50 μM.

II. Cell Based-c-Met Autophosphorylation Assay

A sandwich ELISA assay is used to assess MET autophosphorylation inMKN45 gastric cancer cells, in which MET is constitutively activated.Briefly a monolayer of cells was pre-treated with compounds or thevehicle and then lysed. The MET in a cell lysate was captured by ananti-MET antibody immobilized on a plastic surface. A genericanti-phosphotyrosine antibody or one of several specificanti-phospho-MET antibodies is then allowed to bind captured MET and isdetected using HRP-conjugated secondary antibody. The procedure fordetermining the potency of a compound to inhibit MET autophosphorylationin MKN45 cells comprises the following steps:

Day 1

-   -   1. Coat a 96-well ELISA plate overnight at 4° C. with 100        μl/well of 1 μg/ml capture antibody solution (Af276, R&D).    -   2. Seed a separate 96-well culture plate with MKN45 cells at        90,000 cells/well in 0.1 ml of growth media (RPMI 1640, 10% FBS,        100 ug/mL Pen-Strep, 100 ug/mL L-glutamine, and 10 mM HEPES) and        culture overnight at 37° C./5% CO₂ to 80-90% confluence.

Day 2

-   -   1. Wash the ELISA plate 4× with 200 μl/well of wash buffer        (TBST+0.25% BSA). Incubate the ELISA plate with 200 μl/well of        blocking buffer (TBST+1.5% BSA) for 3-5 hrs at RT.    -   2. Prepare a half-long dilution series of 200× compound in DMSO.        Dilute the series to 10× with assay media (RPMI 1640, 10% FBS,        and 10 mM HEPES).    -   3. Add 10× compound solutions (11 μl/well) to the culture plate        containing MKN45 cells. Incubate the plate at 37° C./5% CO₂ for        60 min.    -   4. Lyse the cells with 100 μl/well of lysis buffer (30 mM Tris,        pH 7.5, 5 mM EDTA, 50 mM NaCl, 30 mM sodium pyrophosphate, 50 mM        NaF, 0.5 mM Na₃VO₄, 0.25 mM potassium        bisperoxo(1,10-phenanthroline)-oxovanadate, 0.5% NP40, 1% Triton        X-100, 10% glycerol, and a protease inhibitor cocktail) at 4° C.        for 90 min.    -   5. Remove blocking buffer from the ELISA plate, wash the plate        4× with 200 μl/well of wash buffer. Transfer 90 μl/well of MKN45        cell lysate from the culture plate to the ELISA plate. Incubate        sealed assay plate at 4° C. with gentle shaking overnight.

Day 3

-   -   1. Wash the ELISA plates 4 times with 200 μl/well wash buffer.    -   2. Incubate with 100 μl/well primary detection antibody (1 μg/ml        in TBST+1% BSA) for 1.5 hours at ambient temperature. The        following primary antibodies have been used: 4G10 from UpState,        anti-pMet(1349) and anti-pMet(1369), both from Biosource.    -   3. Wash the ELISA plates 4 times with wash buffer. Add 100        μl/well of secondary antibody (1:1000 anti-mouse IgG-HRP diluted        in TBST+1% BSA for 4G10, or 1:1000 anti-rabbit IgG-HRP for        anti-pMet(1349) and anti-pMet(1365)). Incubate at room        temperature with gentle mixing for 1.5 hours. Wash 4× with 200        ul/well wash buffer.    -   4. Add 100 μl/well of Quanta Blu reagent (Pierce) and incubate        at room temperature for 8 minutes. Read fluorescence (Excitation        wavelength: 314 nm, emission wavelength: 425 nm) on a Spectramax        Gemini EM plate reader (Molecular Devices).    -   5. IC₅₀ is calculated by fitting the relationship between        compound concentration and fluorescence signal with a        4-parameter logistic equation.

III. MKN45 Cell Proliferation/Viability Assay

MKN45 human gastric cancer cells are known to over-expressconstitutively activated c-met. siRNA-mediated partial knock down ofc-Met was found to induce pronounced growth inhibition and apoptosis inMKN45 cells, suggesting a vital role of c-Met in this cell line. Theassay described here measures the effect of c-Met inhibitors onproliferation/viability of MKN45 cells. The procedure for determiningthe potency of a compound to inhibit MKN45 proliferation/viabilitycomprises the following steps.

On day 1, plate MKN45 cells at 3000 cells/95 μl medium (RPMI/10% FCS,100 mM HEPES, penicillin and streptomycin) per well in a 96 well plate.Maintain the plate in an incubator at 37° C./5% CO₂. Prepare 3-foldserial diluted compound solutions at 1000× of desired finalconcentrations in DMSO.

On day 2, prepare 50× compound solutions by diluting the 1000× compoundsolutions with the medium. Add 5 μl 20× compound solution per well tothe MKN45 cell culture described above. Return the plate to theincubator.

On day 5, add 50 μl lysis buffer (ViaLight Reagents Kit, Catalog No.LT07-221, Cambrex): per well. Lyse the cells at room temperature for 15minutes. Then add 50 μl detection reagent (ViaLight Reagents Kit) andincubate for 3 minutes. The plate is read on a TOPCOUNT (PerkinElmer) inluminescence mode. IC₅₀ is calculated by fitting the relationshipbetween compound concentration and luminescence signal with a4-parameter logistic equation.

IV. HGF-induced cell migration assay

The HGF-Induced Migration of HPAF Pancreatic Cancer Cells was AssessedUsing BD Falcon Fluoroblock 96-Multiwell Insert plates (Cat # 351164, BDDiscovery Labware). The plate consists of wells each of which ispartitioned by a micro-porous membrane into the top and bottom chambers.Pancreatic cancer cells are plated on the top side of the membrane andmigrate to the underside of the membrane in response to chemo-attractantadded to the lower chamber. The cells on the under side of the membraneare labeled with a fluorescent dye and detected by a fluorescence platereader. The procedure for determining the potency of a compound toinhibit cell migration comprises the following steps.

-   -   1. Prepare test compound solutions of 1000× final concentrations        in 100% DMSO    -   2. Dilute the above solutions 50× with DMEM/10% FCS to obtain        compound solutions 20× of the final concentrations.    -   3. Fill each lower chamber of a Fluoroblock 96-Muntiwell Insert        plate with 180 μl DMEM/10% FCS, and plate 8,000 HPAF pancreatic        cancer cells in 50 ul DMEM/10% FCS in each upper chamber.    -   4. 1-2 hours after plating, add 2.5 μl and 10 μl of a 20×        compound solution to the upper and the lower chamber        respectively. Incubate the plate at 37° C. for 60 min, and then        add concentrated HGF to lower chamber to a final HGF        concentration of 15 ng/ml. The insert plates are incubated        overnight for 20 hours.    -   5. An aliquot of a concentrated Calcein dye (Molecular Probes)        is added to each lower chamber to give 5 μg/ml final dye        concentration and the cells are labeled for 1 hour. Wash each        lower chamber with 200 μl DMEM/10% FCS    -   6. Read fluorescence on a Victor reader (PerkinElmer) in bottom        read mode (Excitation wave length: 485 nm, emission wavelength:        535 nm).    -   7. IC₅₀ is calculated by fitting the relationship between        compound concentration and fluorescence signal with a        4-parameter logistic equation.        V. K₁ and k_(inact) Determination for Time-Dependent Inhibition        of CYP3A4

The time-dependant inhibition assay for CYP3A4 was performed in twosteps, a preincubation step where the test compound was incubated withhuman liver microsomes and the secondary incubation period where CYP3A4substrate, testosterone was added to the preincubate to measure residualCYP3A4 activity. Wells contained human liver microsomes (42.5 μl, 2.35mg/ml) which were diluted from a stock (20 mg/ml) in potassium phosphatebuffer (50 mM, pH 7.4) such that the final concentration in the 50 μlpreincubation was 2 mg/ml. The wells also contained test compound (2.5μl at 20 times the incubation concentration) in a solvent mixture ofDMSO:water:methanol (10:50:40) and the same solvent in the absence ofthe test compound was used as the control. The final concentrations ofthe test compound in the preincubations were 1.56, 3.13, 6.25, 12.5, 25,50 and 100 μM. The preincubation times used were 0, 5, 10, 15, and 20min. Separate preincubations were used for each preincubation timepoint. The rack containing the wells was pre-warmed for 30 min at 37° C.in an incubator that was gently shaken and the temperature wasmaintained at 37° C. for the duration of the incubations. Thepreincubation period was initiated by the addition of NADPH (5 μl, 10mM) that had been pre-warmed to 37° C. for ten minutes. Following thepreincubation step, the secondary incubations were initiated byperforming a 10-fold dilution of the preincubate using 450 μl of apre-warmed (37° C.) solution of NADPH (1 mM) and testosterone (222 μM)in potassium phosphate (50 mM, pH 7.4) The final concentration of NADPHand testosterone in the 500 μl incubation was 1 mM and 200 μM,respectively. After a 10 min incubation, each well was quenched with 1ml of acetonitrile containing the internal standard, cortisone (0.6μg/ml) and placed on ice. The rack was centrifuged at 3202 g for 10 minand 200 μl of the supernatant was diluted with 100 μl of water, mixedwell and analyzed by LC/MS-MS.

Samples (10 μl) were injected onto a C₁₈ column (2.0 mm×30 mm, 3 μmparticle size) and eluted using water containing 0.1% formic acid as theaqueous mobile phase (A), and acetonitrile containing 0.1% formic acidas the organic phase (B), according to the following gradient table:

Time Flow Rate (min) (ml/min) % A % B 0.00 0.85 98 2 0.02 0.85 98 2 3.020.85 2 98 3.52 0.85 2 98 3.53 0.85 98 2The eluent from the column was sent to the mass spectrometer andspecific multiple reaction monitoring transitions for testosteronemetabolite, 613-OH testosterone (305 m/z>269 m/z) and cortisone (361m/z>185 m/z) were used for MS/MS detection. Integrated area ratios ofthe analyte (6β-OH testosterone) to the internal standard (cortisone)were analyzed by nonlinear regression to calculate K₁ and k_(inact).

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be illustrative of the invention and not limiting of thereasonable scope thereof.

Example 1

Step 1: 2-[(E/Z)-2-(4-bromophenyl)vinyl]-3-carboxy-5-chloropyridiniumchloride

Potassium tert-butoxide (1M solution in THF, 60 mL, 60 mmol) was addedto a solution of 4-bromobenzaldehyde (5.6 g, 30 mmol) and methyl5-chloro-2-methylnicotinate (Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.;Dormer, P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. J. Org. Chem.2001, 66, 4194-4199) (5.6 g, 30 mmol) in 200 mL THF at 0° C. The mixturewas allowed to warm to ambient temperature and stirred for 12 hours. Thereaction slurry was concentrated to give yellow/orange solids, then 50mL of water and 50 mL of 6N HCl were added. After stirring the resultingslurry for 30 minutes, 200 mL of EtOH was added and the slurry wasstirred for 4 hours. The slurry was filtered and dried to afford thetitle compound. ¹H NMR (600 MHz, DMSO-D₆) δ 8.76 (d, 1H); 8.22 (d, 1H);8.02 (d, 1H); 7.79 (d, 1H); 7.60-7.54 (m, 4H). LRMS (APCI) calculatedfor C₁₄H₁₀BrClNO₂ [M+H]⁺, 338.0; found 337.9.

Step 2: 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 1)

2-[(E/Z)-2-(4-bromophenyl)vinyl]-3-carboxy-5-chloropyridinium chloride(11.2 g, 29.9 mmol) was added to 50 mL of polyphosphoric acid and heatedto 200° C. After 12 hours, the solution was poured into ice and 250 mLof 5N sodium hydroxide solution, then 5N sodium hydroxide solution wasadded to adjust to pH 10. The mixture was diluted in 2 L ofdichloromethane, 100 g of Celite were added and the suspension wasstirred for 15 minutes. The solids were filtered through a sinteredglass funnel and discarded. The liquid phase was poured into aseparatory funnel and the organic layer was isolated. The organic layerwas dried with magnesium sulfate, filtered, and concentrated to affordCompound 1. ¹H NMR (600 MHz, CDCl₃) δ 8.82 (d, 1H); 8.50 (d, 1H); 8.41(d, 1H); 7.80 (dd, 1H); 7.48 (d, 1H); 7.35 (d, 1H); 7.20 (d, 1H). LRMS(APCI) calculated for C₁₄H₈BrClNO [M+H]⁺, 320.0; found 320.0.

Example 2N,N-Dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(Compound 2-4)

Step 1: Methyl [(dimethylamino)sulfonyl]acetate (Compound 2-1)

Dimethylamine in THF (57.9 ml, 116 mmol) was dissolved indichloromethane (29.0 ml) and cooled to 0° C. Then, methyl(chlorosulfonyl)acetate (prepared according to: Szymonifka, M. J.; Heck,J. V. Tet. Lett. 1989, 30, 2869-72.) (10.0 g, 57.9 mmol) was addeddropwise as a solution in dichloromethane (29.0 ml), while maintainingthe temperature below 5° C. The resulting solution was allowed to warmto room temperature over the course of 2 h. Then, brine (200 mL) wasadded and the aqueous phase was extracted with dichloromethane (3×100mL). The combined organics were dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (EtOAc/Hexanes gradient) to affordthe title compound as a yellow liquid. ¹H NMR (600 MHz, DMSO-D₆) δ 4.25(s, 2H); 3.68 (s, 3H); 2.78 (s, 6H). LRMS (APCI) calculated forC₅H₁₂NO₄S [M+H]⁺, 182.0; found 182.0.

Step 2: Methyl(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)[(dimethylamino)sulfonyl]acetate(Compound 2-2)

A 200 mL round bottom flask was charged with methyl[(dimethylamino)sulfonyl]acetate (5.26 g, 29.0 mmol) and dioxane (77ml), cooled to 0° C. and then sodium hydride (2.321 g, 58.0 mmol) wasadded in one portion. After 15 min., the mixture was warmed to roomtemperature and7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.20 g,19.34 mmol) was added followed by Pd₂(dba)₃ (0.708 g, 0.774 mmol) andtriphenylphosphine (1.217 g, 4.64 mmol). The resulting suspension wasdegassed by sparging with nitrogen for 30 min. Then, the mixture washeated to 70° C. and left to stir overnight. The reaction was thencooled to room temperature, poured into brine (500 mL) and extractedwith dichloromethane (3×150 mL). The combined organics were then driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel(EtOAc/Hexanes gradient) to afford the title compound as a yellow oilthat solidified to a yellow solid upon standing. ¹H NMR (600 MHz,DMSO-D₆) δ 9.00 (d, 1H); 8.49 (d, 1H); 8.47 (d, 1H); 8.07 (dd, 1H); 7.88(d, 1H); 7.48 (d, 1H); 7.34 (d, 1H); 6.05 (s, 1H); 3.75 (s, 3H); 2.68(s, 6H). LRMS (APCI) calculated for C₁₉H₁₈ClN₂O₅S [M+H]⁺, 421.1; found421.0.

Step 3:1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylmethanesulfonamide(Compound 2-3)

Methyl(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)[(dimethylamino)sulfonyl]acetate(2.04 g, 4.85 mmol) was dissolved in a mixture of AcOH (24.24 ml) and 6MHCl (24.24 ml) and heated to 100° C. for 3 h. The solution was thencooled to room temperature, basified with saturated aqueous sodiumhydrogen carbonate and extracted with dichloromethane (3×50 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (EtOAc/Hexanes gradient) to afford thetitle compound as a yellow solid. ¹H NMR (600 MHz, DMSO-D₆) δ 8.99 (d,1H); 8.48 (d, 1H); 8.21 (s, 1H); 7.84 (m, 2H); 7.49 (d, 1H); 7.33 (d,1H); 4.63 (s, 2H); 2.74 (s, 6H). LRMS (APCI) calculated forC₁₇H₁₆ClN₂O₃S [M+H]⁺, 363.1; found 363.1.

Step 4:N,N-Dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(Compound 2-4)

1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylmethanesulfonamide(1.44 g, 3.97 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole(1.239 g, 5.95 mmol), tri-t-butylphosphonium tetrafluoroborate (0.104 g,0.357 mmol), Pd₂(dba)₃ (0.145 g, 0.159 mmol), and potassium fluoride(0.761 g, 13.10 mmol) were combined as solids and then placed under anitrogen atmosphere. DMF (39.7 ml) was added and the resultingsuspension was heated to 130° C. and left to stir for 1 h. Then, thereaction was cooled to room temperature and partitioned betweensaturated aqueous sodium hydrogen carbonate (250 mL) and dichloromethane(250 mL). The organic layer was dried over anhydrous Na₂ SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica (EtOAc+10% MeOH/Hexanes gradient) toafford the title compound as a yellow solid. ¹H NMR (600 MHz, DMSO-D₆) δ9.21 (d, 1H); 8.54 (d, 1H); 8.47 (s, 1H); 8.19 (s, 1H); 8.14 (s, 1H);7.81 (m, 2H); 7.40 (d, 1H); 7.32 (d, 1H); 4.63 (s, 2H); 3.88 (s, 3H);2.74 (s, 6H). LRMS (APCI) calculated for C₂₁H₂₁N₄O₃S [M+H]⁺, 409.1;found 409.1.

Example 3

1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[45]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide(Compound 3-1)

Cesium carbonate (80 mg, 0.245 mmol) was added to a solution ofN,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(50 mg, 0.122 mmol) and aniline (559 μL, 6.12 mmol) in dioxane (1113 μl)and water (111 μl) in a 0.5 ml to 2 ml microwave vial. The vial was thensealed and the mixture was heated to 180° C. for 3 h. After cooling toroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was purified by preparative HPLC Reverse phase(C-18), eluting with Acetonitrile/Water+0.1% TFA, to afford the titlecompound as a yellow solid. ¹H NMR (600 MHz, DMSO-D₆) δ 9.84 (br s, 1H);9.22 (d, 1H); 8.51 (d, 1H); 8.48 (s, 1H); 8.15 (s, 1H); 8.04 (d, 1H);7.76 (d, 1H); 7.63 (dd, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.27 (m, 2H);7.16 (dd, 2H); 7.00 (m, 1H); 4.68 (s, 2H); 3.89 (s, 3H). LRMS (APCI)calculated for C₂₅H₂₁N₄O₃S [M+H]⁺, 457.1; found 457.1.

The compounds listed below in Table 1 were prepared in analogy to thepreparation of Compound 3-1 fromN,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(vide supra):

TABLE 1 Comp. [M + H] + [M + H] + # Structure Name calc obs 3-2

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide381.1 381.1 3-3

N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide395.1 395.1 3-4

N-benzyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-yl]methanesulfonamide471.2 471.1 3-5

N-(1,4-dioxan-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide481.2 481.1 3-6

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1-phenylethyl)methane-sulfonamide;isolatedas the TFA salt 485.2 485.1 3-7

N-(4-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide485.2 485.1 3-8

N-(3-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;isolatedas the TFAsalt 485.2 485.1 3-9

N-(2-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;isolatedas the TFAsalt 485.2 485.1 3-10

N-(3-methoxybenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide501.2 501.1 3-11

N-(4-methoxybenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide501.2 501.1 3-12

N-(4-fluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideisolatedas the TFAsalt 489.2 489.1 3-13

N-(3,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide507.1 507.1 3-14

N-(2,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;isolatedas the TFAsalt 507.1 507.1 3-15

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(2-phenylethyl)methanesulfonamide;isolatedas the TFA salt 485.2 485.1 3-16

N-(cyclohexylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideisolatedas the TFAsalt 477.2 477.2 3-17

N-isobutyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide437.2 437.1 3-18

N-(3-methylbutyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideisolatedas the TFAsalt 451.2 451.1 3-19

N-[(1-methyl-1H-imidazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideisolatedas the TFAsalt 475.2 475.1 3-20

N-(3-furylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideisolatedas the TFAsalt 461.1 461.1 3-21

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-propylmethanesulfonamideisolatedas theTFA salt 423.2 423.1 3-22

N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide489.2 489.1 3-23

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-3-ylmethyl)methane-sulfonamide472.1 472.1 3-24

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-methylpyridin-2-yl)methyl]methanesulfonamideisolatedasthe TFA salt 486.2 486.1 3-25

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}methanesulfonamideisolatedasthe TFA salt 540.1 540.1 3-26

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-4-ylmethyl)methanesulfonamide472.1 472.1

Example 4

1,1-Difluoro-N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(Compound 4-1) and1-Fluoro-N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,51cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(Compound 4-2)

To a cooled −78° C. solution ofN,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide(21.1 mg, 0.052 mmol) and N-fluorobenzenesulfonimide (40.7 mg, 0.129mmol) in THF (2066 μl) was added NaHMDS 1.0M in THF (114 μl, 0.114 mmol)dropwise over the course of 30 min. via syringe pump. After 2 h at −78°C., the reaction was allowed to come to room temperature over the courseof 2 h. Then, the reaction was acidified with saturated aqueous ammoniumchloride (75 mL) and extracted with dichloromethane (3×75 mL). Thecombined organics were dried over anhydrous Na₂ SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC Reverse phase (C-18), eluting withAcetonitrile/Water+0.1% TFA, to afford the slower eluting Compound 4-1as a yellow solid and the faster eluting Compound 4-2 as a yellow solid.LRMS (APCI) calculated for Compound 4-1 C₂₁H₁₉F₂N₄O₃S [M+H]⁺, 445.1;found 445.1. LRMS (APCI) calculated for Compound 4-2 C₂₁H₂₀FN₄O₃S[M+H]⁺, 427.1; found 427.1.

Example 5N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide(Compound 5-5)

Step 1: Methyl {[methyl(phenyl)amino]sulfonyl}acetate (Compound 5-1)

Chlorine gas was passed through a suspension of 230 g of ice, CH₂Cl₂(457 ml) and methyl thioglycolate (86 ml, 942 mmol), cooling with anice/water bath to maintain an internal temperature below 30° C. Afterapproximately six hours, the yellow/green color of the dissolvedchlorine persisted for 30 minutes after gas flow was stopped and passingadditional chlorine gas was no longer exothermic. The cooling bath wasthen removed and the biphasic mixture was allowed to stir at ambienttemperature for 1 h before being sparged with nitrogen for 20 minutes.The layers were then separated and the organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure to provide theintermediate methyl (chlorosulfonyl)acetate (160 g, 927 mmol) as ayellow oil. A portion of the intermediate methyl (chlorosulfonyl)acetate(100 g, 579 mmol) was added dropwise as a solution in CH₂Cl₂ (290 ml) toa stirring −15° C. solution of N-methylaniline (124 g, 1159 mmol)dissolved in CH₂Cl₂ (290 ml). The rate of addition was adjusted tomaintain the internal temperature below 5° C. After the addition wascomplete, the reaction mixture was allowed to warm to room temperatureover the course of 2h and 1 M HCl (1000 mL) was added and the aqueousphase was extracted with dichloromethane (2×500 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting oil was seed crystallized toafford a brown solid. Recrystallization from hot ethanol (320 mL)provided the title compound as an off-white solid. ¹H NMR (600 MHz,DMSO-D₆) δ 7.40 (m, 4H); 7.31 (m, 1H); 4.30 (s, 2H); 3.65 (s, 3H); 3.26(s, 3H). LRMS (APCI) calculated for C₂₅H₂₁N₄O₃S [M+H]⁺, 244.1; found244.0.

Step 2: Methyl(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl){[methyl(phenyl)amino]sulfonyl}acetate(Compound 5-2)

Sodium tert-butoxide (8.99 g, 94 mmol) was added in one portion to a 250mL flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (7.59g, 31.2 mmol) and dioxane (125 ml) at room temperature. After 15 min.,7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10.00 g,31.2 mmol) was added followed by palladium(II) acetate (0.350 g, 1.560mmol) and tri-t-butylphosphonium tetrafluoroborate (1.358 g, 4.68 mmol).The resulting suspension was degassed by sparging with nitrogen for 30min. Then, the mixture was heated to 90° C. in a pre-warmed bath andleft to stir for 1 h. Then, the reaction mixture was cooled to roomtemperature, acidified with 1N HCl (100 mL), basified with saturatedaqueous sodium hydrogen carbonate (400 mL) and extracted withdichloromethane (3×250 mL). The combined organics were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel(EtOAc/Hexanes gradient) to afford the title compound as a yellow foam.¹H NMR (600 MHz, DMSO-D₆) δ 8.99 (d, 1H); 8.46 (d, 1H); 8.42 (d, 1H);8.03 (dd, 1H); 7.81 (d, 1H); 7.44 (d, 1H); 7.33 (d, 1H); 7.22 (m, 2H);7.17 (m, 2H); 7.11 (m, 1H); 6.10 (s, 1H); 3.71 (s, 3H); 3.20 (s, 3H).LRMS (APCI) calculated for C₂₄H₂₀ClN₂O₅S [M+H]⁺, 483.1; found 483.0.

Step 3:1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide(Compound 5-3)

Sodium tert-butoxide (47.4 g, 493 mmol) was added in one portion to a 1L flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (40.0g, 164 mmol) and dissolved in dioxane (658 ml) at 0° C. After 15 min.,7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (52.7 g,164 mmol) was added followed by palladium(II) acetate (1.846 g, 8.22mmol) and tri-t-butylphosphonium tetrafluoroborate (7.16 g, 24.66 mmol).The resulting suspension was degassed by sparging with nitrogen for 30min. Then, the mixture was heated to 90° C. in a pre-warmed bath andleft to stir for 1 h. Then, the reaction flask was cooled to 50° C., 1MNaOH (500 mL) was added and the solution was stirred for 1 h. Then, thesolution was diluted with saturated aqueous sodium hydrogen carbonate(800 mL) and extracted with dichloromethane (3×500 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (EtOAc/Hexanes gradient) to afford the title compound asa pale yellow solid. ¹H NMR (600 MHz, DMSO-D₆) δ 8.99 (d, 1H); 8.47 (m,1H); 8.17 (s, 1H); 7.81 (s, 2H); 7.47 (d, 1H); 7.32 (m, 5H); 7.21 (m,1H); 4.75 (s, 2H); 3.24 (s, 3H). LRMS (APCI) calculated forC₂₂H₁₈ClN₂O₃S [M+H]⁺, 425.1; found 425.0.

Step 4:N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide(Compound 5-4)

1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide(4.4 g, 10.36 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole(2.59 g, 12.43 mmol), potassium fluoride (1.985 g, 34.2 mmol),tri-t-butylphosphonium tetrafluoroborate (0.270 g, 0.932 mmol), andPd₂(dba)₃ (0.379 g, 0.414 mmol) were combined as solids and placed undera nitrogen atmosphere. DMF (104 ml) was added, the mixture was degassed,and then the reaction was heated to 130° C. with stirring for 2 h. Aftercooling to room temperature, the mixture was poured into aqueous sodiumhydrogen carbonate (saturated, 250 mL) and extracted withdichloromethane (4×250 mL). The organic extracts were combined, driedover Na₂ SO₄, and concentrated under reduced pressure. The residue wasthen dissolved in hot dioxane (500 mL). Hexanes were added until aprecipitate formed. After standing at room temperature overnight, theprecipitate was collected to afford the title compound as a gray solid.¹H NMR (600 MHz, DMSO-D₆) δ 9.22 (d, 1H); 8.53 (d, 1H); 8.47 (s, 1H);8.15 (s, 1H); 8.14 (d, 1H); 7.78 (m, 2H); 7.39 (d, 1H); 7.32 (m, 5H);7.20 (m, 1H); 4.75 (s, 2H); 3.88 (s, 3H); 3.23 (s, 3H). LRMS (APCI)calculated for C₂₁H₂₁N₄O₃S [M+H]⁺, 409.1; found 409.1.

Step 5:1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-3-ylmethanesulfonamide(Compound 5-5)

N-Methyl-2-pyrrolidinone (3 ml) was added toN-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide(150 mg, 0.319 mmol) and pyridin-3-amine (150 mg, 1.594 mmol) in a vial.The vial was sealed and the resulting solution was heated to 180° C.with stirring. After 2.25 h., the reaction was cooled to roomtemperature and diluted in DMSO and water. The resulting solution wasfiltered and purified by preparative HPLC Reverse phase (C-18), elutingwith Acetonitrile/Water+0.05% TFA, to afford the title compound as abrown solid. ¹H NMR (600 MHz, DMSO-D₆) δ 9.21 (d, 1H); 8.52 (d, 1H);8.48 (s, 1H); 8.33 (d, 1H); 8.16 (d, 1H); 8.15 (s, 1H); 8.07 (s, 1H);7.77 (d, 1H); 7.68 (dd, 1H); 7.52 (m, 1H); 7.35 (d, 1H); 7.32 (d, 1H);7.25 (m, 1H); 4.77 (s, 2H); 3.89 (s, 3H). LRMS (APCI) calculated forC₂₄H₁₉N₅O₃S [M+H]⁺, 458.1; found 458.1.

Example 6

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide(Compound 6-1)

N-Methyl-2-pyrrolidinone (13.3 ml) was added toN-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide(627 mg, 1.33 mmol) and 2-aminomethylthiazole dichloride (1004 mg, 6.66mmol) in a vial. Triethylamine (1.86 mL, 13.3 mmol) was added and thevial was sealed, the resulting solution was heated to 180° C. withstirring. After 1.5 h., the reaction was cooled to room temperature anddiluted in DMSO and water. The resulting solution was purified bypreparative HPLC Reverse phase (C-18), eluting withAcetonitrile/Water+0.05% TFA, to afford the title compound as a yellowsolid. ¹H NMR (600 MHz, DMSO-D₆) δ 9.22 (d, 1H); 8.54 (d, 1H); 8.48 (s,1H); 8.16 (m, 3H); 7.81 (d, 1H); 7.78 (dd, 1H); 7.71 (d, 1H); 7.63 (d,1H); 7.41 (d, 1H); 7.33 (d, 1H); 4.67 (s, 2H); 4.43 (d, 2H); 3.88 (s,3H). LRMS (APCI) calculated for C₂₄H₁₉N₅O₃S [M+H]⁺, 478.1; found 478.0.

Synthesis of Compounds in Table 2 (General Procedure):

Compounds in Table 2 were prepared in analogy to the proceduresdescribed for the preparation of Compounds 5-6 and 6-1 as follows:Either Compound 5-4 (1.0 equivalents) or Compound 7-1 (1.0 equivalents)and either an amine (1.0 to 5.0 equivalents) or an amine salt (1.0 to5.0 equivalents) were combined in a vial with enoughN-methyl-2-pyrrolidinone to generate a 0.1M solution of either Compound5-4 or Compound 7-1. Triethylamine (1:1 molar ratio to the amine salt)was then added to reactions utilizing amine salts composed of a 1:1ratio of amine to acid. Triethylamine (2:1 molar ratio to the aminesalt) was then added to reactions utilizing amine salts composed of a1:2 ratio of amine to acid. No triethylamine was added when aminefreebases were employed. The vial was then sealed and the resultingsolution or suspension was heated and stirred at 180° C. withconventional heating. After the reaction was judged to be complete byLCMS analysis, the reaction was cooled to room temperature and dilutedin DMSO and water. The resulting solution was filtered and purified bypreparative HPLC Reverse phase (C-18), eluting withAcetonitrile/Water+0.05% TFA, to afford the title compounds.

TABLE 2 [M + H] [M + H] Comp. + + # Structure Name calcul obser 6-2

N-[(5-methylpyrazin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide487.2 487.1 6-3

N-[(5-methyl-isoxazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide476.2 476.1 6-4

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-1,2,4-triazol-5-ylmethyl)methane-sulfonamide462.1 462.1 6-5

N-(1H-benzimidazol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide511.2 511.1 6-6

N-(1H-imidazol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide461.1 461.1 6-7

N-(1H-indol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide510.2 510.1 6-8

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(1,3-thiazol-5-ylmethyl)-methanesulfonamide478.1 478.1 6-9

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-[(3-methylpyridin-4-yl)-methyl]methane-sulfonamide486.2 486.1 6-10

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(3-thienylmethyl)methanesulfonamide477.1 477.1 6-11

N-(imidazo[1,2-a]pyridin-2-yl-methyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide511.2 511.1 6-12

N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide489.2 489.1 6-13

N-[(3-methyl-isoxazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide476.1 476.1 6-14

N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide489.2 489.1 6-15

N-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide525.2 525.1 6-16

N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide512.2 512.1 6-17

N-(imidazo[2,1-b][1,3]thiazol-6-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]yridine-7-yl]-methanesulfonamide 517.1 517.1 6-18

N-[(3-methyl-imidazo[2,1-b][1,3]-thiazol-6-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-methanesulfonamide 531.1 531.1 6-19

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-[(3-phenylisoxazol-5-yl)methyl]methanesulfonamide 538.2538.1 6-20

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]-methanesulfonamide554.1 554.1 6-21

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-methanesulfonamide492.1 492.1 6-22

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-methanesulfonamide492.1 492.1 6-23

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-methanesulfonamide476.2 476.1 6-24

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-[(3-pyridin-2-ylisoxazol-5-yl)-methyl]-methanesulfonamide539.2 539.2 6-25

N-[4-(1H-imidazol-4-yl)benzyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]yridine-7-yl]methanesulfonamide 537.2 537.1 6-26

N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-methanesulfonamide 475.2 475.1 6-27

N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]yridine-7-yl]-methanesulfonamide 478.1 478.0 6-28

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-{[4-(trifluoromethyl)-pyridin-2-yl]methyl}-methanesulfonamide;isolatedas theHCl salt 540.1 540.1 6-29

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-{[5-(trifluoromethyl)-pyridin-2-yl]methyl}-methanesulfonamide;isolatedas theHCl salt 540.1 540.1 6-30

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-{[6-(trifluoromethyl)-pyridin-2-yl]methyl}-methanesulfonamide;isolatedas theHCl salt 540.1 540.1 6-31

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(2-morpholin-4-yl-2-oxoethyl)methane-sulfonamide508.2 508.1 6-32

N~2~-({[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]yridine-7-yl]-methyl}sulfonyl)-glycinamide 438.1 438.1 6-33

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-{[2-(2-thienyl)-1,3-thiazol-4-yl]methyl}-methanesulfonamide560.1 560.1 6-34

N-[(2-benzyl-1,3-thiazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-methanesuifonamide 568.2 568.1 6-35

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-(1H-pyrazol-3-ylmethyl)methane-sulfonamide 461.1 461.16-36

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]yridine-7-yl]-N-(1,2,3-thiadiazol-4-ylmethyl)methane-sulfonamide 479.1479.1 6-37

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(pyridazin-4-ylmethyl)methanesulfonamide473.1 473.1 6-38

N-[(1-methyl-1H-pyrazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide475.2 475.1 6-39

N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide475.2 475.1 6-40

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridin-3-ylmethyl)-methanesulfonamide540.2 540.2 6-41

N-[(1-methyl-1H-imidazol-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide475.2 475.1 6-42

N-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-methanesulfonamide501.2 501.1 6-43

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(1,3-oxazol-2-ylmethyl)-methanesulfonamide462.1 462.1 6-44

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-[(3-phenyl-1,2,4-oxa-diazol-5-yl)methyl]-methanesulfonamide539.2 539.1 6-45

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridine-7-yl]-N-[(3-phenyl-1H-pyrazol-4-yl)methyl]-methanesulfonamide537.2 537.1 6-46

N-(6,7-dihydro-5H-cyclopenta[b]pyridine-3-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridine-7-yl]-methanesulfonamide512.2 512.1 6-47

N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridine-7-yl]-methanesulfonamide489.2 489.1 6-48

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(1H-pyrazol-5-ylmethyl)-methanesulfonamide461.1 461.1 6-49

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(1H-1,2,3-triazol-4-ylmethyl)methane-sulfonamide462.1 462.1 6-50

N-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide477.1 477.1 6-51

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(pyrimidin-2-yl-methyl)methane-sulfonamide473.1 473.1 6-52

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(pyrimidin-4-ylmethyl)methane-sulfonamide473.1 473.1 6-53

N-[(4,6-dimethyl-pyrimidin-2-yl)-methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-methanesulfonamide501.2 501.1 6-54

N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide478.1 478.0 6-55

N-[(3,5-difluoro-pyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-methanesulfonamide508.1 508.1 6-56

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-4-ylmethyl)methanesulfonamide478.1 478.0 6-57

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(pyrazin-2-ylmethyl)-methanesulfonamide473.1 473.0 6-58

N-(imidazo[1,2-a]-pyridin-3-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide511.2 511.0 6-59

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(1,3-oxazol-4-ylmethyl)-methanesulfonamide462.1 462.0 6-60

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(pyrimidin-5-ylmethyl)methane-sulfonamide473.1 473.0 6-61

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-phenyl-1,3-thiazol-5-yl)methyl]-methanesulfonamide554.1 554.0 6-62

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-[(6-methylpyridin-2-yl)methyl]methane-sulfonamide486.2 486.1 6-63

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)methane-sulfonamide527.2 527.0 6-64

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(1-pyridin-2-ylethyl)-methanesulfonamide486.2 486.0 6-65

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N-(pyridazin-3-yl-methyl)methane-sulfonamide473.1 473.1 6-66

N-[(5-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide490.1 490.1 6-67

N-[(3-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-y1)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide 490.1 490.1

N-[(6-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide 490.1 490.1 6-68

N-[(6-bromopyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide550.1 550.0 6-69

N-[(5-chloropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide506.1 506.1 6-70

N-[(6-chloropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide506.1 506.1 6-71

N-ethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)-methanesulfonamide500.2 500.1 6-72

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-4-ylmethane-sulfonamide;isolatedas the TFAsalt 458.1 458.1 6-73

N-(2-hydroxyethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)-methanesulfonamide516.2 516.1 6-74

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-2-ylmethane-sulfonamide458.1 458.1 6-75

N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-methanesulfonamide498.2 498.1 6-76

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)-ethanesulfonamide486.2 486.0 EXAMPLE 7

N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylethanesulfonamide(Compound 7-1)

Lithium bis(trimethylsilyl)amide (1063 μl, 1.063 mmol, 1 M in THF) wasadded to a solution ofN-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide(250 mg, 0.531 mmol) in THF (5.3 mL) at −78° C. After stirring for 30minutes at −78° C., the solution was warmed to room temperature and thencooled to −78° C. before adding a solution of methyl iodide (100 μl,1.594 mmol) in THF (3.75 mL) dropwise. After 2 hours, the reaction waswarmed to room temperature, acidified with aqueous ammonium chloride(saturated) and water (75 mL), then extracted with dichloromethane(3×100 mL). The combined organic extracts were washed with brine (50mL×2), dried over anhydrous Na₂ SO₄, filtered and concentrated underreduced pressure to afford the title compound as a yellow solid. LRMS(APCI) calculated for C₂₇H₂₄N₄O₃S [M+H]⁺, 485.2; found 485.1.

Example 81-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide(Compound 8-2)

Step 1:1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(pyridin-2-ylmethyl)methanesulfonamide(Compound 8-1)

2-Aminomethylpyridine (55.9 ml, 546 mmol) was added to a solution of1-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide(51.6 g, 121 mmol) in N-methyl-2-pyrrolidinone (1214 ml) at roomtemperature. The solution Was then heated to 130-135° C. for 2 h in apre-warmed oil bath. The solution was then cooled to room temperatureand poured into aqueous sodium hydrogen carbonate (saturated, 3.0 L) and500 mL ice-water and extracted with ethyl acetate (3×500 mL). Thecombined organics were dried over anhydrous Na₂ SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (EtOAc/Hexanes gradient) to afford thetitle compound as a yellow solid. ¹H NMR (600 MHz, DMSO-D₆) δ 8.99 (d,1H); 8.47 (d, 1H); 8.46 (m, 1H); 8.16 (d, 1H); 7.81 (m, 3H); 7.76 (m,1H); 7.49 (d, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.63 (s,2H); 4.22 (d, 2H). LRMS (APCI) calculated for C₂₁H₁₇ClN₃O₃S [M+H]⁺,426.1; found 426.0.

Step 2:1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide(Compound 8-2)

1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(pyridin-2-ylmethyl)methanesulfonamide(31.0 g, 72.8 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole(22.72 g, 109 mmol), potassium fluoride (13.96 g, 240 mmol),tri-t-butylphosphonium tetrafluoroborate (2.112 g, 7.28 mmol), andPd₂(dba)₃ (3.33 g, 3.64 mmol) were placed in a flask under an atmosphereof argon. DMF (364 ml) was added and argon was bubbled through thesolution for several minutes. The solution was then heated at 130° C.for 6 h. The mixture was then cooled to room temperature, aqueous sodiumhydrogen carbonate (saturated, 2000 mL) was added and the mixture wasextracted with ethyl acatate (10×500 mL). The combined organic fractionswere dried (anhydrous Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC Reverse phase(C-18), eluting with Acetonitrile/Water+0.05% TFA to afford the titlecompound as a pale yellow solid. ¹H NMR (600 MHz, DMSO-D₆) δ 9.21 (d,1H); 8.53 (d, 1H); 8.47 (m, 1H); 8.46 (m, 1H); 8.15 (d, 1H); 8.14 (s,1H); 7.78 (m, 4H); 7.39 (m, 2H); 7.32 (d, 1H); 7.24 (m, 1H); 4.63 (s,2H); 4.22 (d, 1H); 3.88 (s, 3H). LRMS (APCI) calculated for C₂₅H₂₁N₅O₃S[M+H]⁺, 472.1; found 472.1.

Example 9

Step 1:1-(2,4-dimethoxyphenyl)-N-(1,2,3-thiadiazol-4-ylmethyl)methanamine

To a solution of 1,2,3-thiadiazole-4-carboxaldehyde (750 mg, 6.57 mmol)and 2,4-dimethoxybenzylamine (1086 μl, 7.23 mmol) in 1,2-dichloroethane(13.1 mL) at 0° C. was added molecular sieves (powdered, 4A) (2.50 g,6.57 mmol) followed by sodium triacetoxyborohydride (1950 mg, 9.20mmol). The reaction was allowed to warm to room temperature withstirring overnight. Then, the resulting suspension was poured intodichloromethane (75 mL) and aqueous sodium hydrogen carbonate(saturated, 75 mL). The layers were mixed and then filtered throughcelite. The aqueous layer was then extracted with dichloromethane (3×50mL) and the combined organics were dried over anhydrous Na₂ SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (EtOAc/Hexanes+1%triethylamine gradient) to afford the title compound as a pale yellowliquid. LRMS (APCI) calculated for C₁₂H₁₆N₃O₂S [M+H]⁺, 266.1; found266.1.

Step 2: 1-(1,2,3-Thiadiazol-4-yl)methanamine (Compound 9-1)

Trifluoroacetic acid (2.91 ml) was added to a solution of1-(2,4-dimethoxyphenyl)-N-(1,2,3-thiadiazol-4-ylmethyl)methanamine(0.483 g, 1.820 mmol) in dichloromethane (4.37 ml) at 0° C. After 1 h,the reaction was warmed to room temperature and allowed to stir for anadditional 3 h. Then, the reaction was heated to 60-70° C. in a sealedtube for 96 h. The reaction mixture was then cooled to room temperatureand concentrated under reduced pressure. The residue was taken up indichloromethane (20 mL) and passed through a series of sevenStratoSpheres SPE PL-HCO3 MP SPE columns (0.9 mmol HCO₃/tube), rinsingwith methanol. The filtrates were combined and concentrated underreduced pressure to afford the title compound as a colorless oil. ¹H NMR(600 MHz, DMSO-D₆) δ 9.21 (d, 1H); 8.53 (d, 1H); 8.47 (m, 1H); 8.46 (m,1H); 8.15 (d, 1H); 8.14 (s, 1H); 7.78 (m, 4H); 7.39 (m, 2H); 7.32 (d,1H); 7.24 (m, 1H); 4.63 (s, 2H); 4.22 (d, 1H); 3.88 (s, 3H). LRMS (APCI)calculated for C₃H₆N₃S [M+H]⁺, 116.0; found 116.1.

Example 10

1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(1-oxidopyridin-2-yl)methyl]methanesulfonamide(Compound 10-1)

3-Chloroperoxybenzoic acid (26.1 mg, 0.106 mmol) was added to a solutionof1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide(50 mg, 0.106 mmol) in dichloromethane (1.06 mL) at 0 C. After 15 min.,the reaction was allowed to warm to room temperature and stirring wascontinued for 6 hr. Then, aqueous sodium hydrogen carbonate (saturated,50 mL) was added, and the mixture was extracted with dichloromethane(3×50 mL). The combined organic extracts were washed with aqueous sodiumhydrogen carbonate (saturated, 2×75 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by preparative HPLC Reverse phase (C-18), eluting withAcetonitrile/Water+0.05% TFA, to afford the title compound as a yellowsolid. ¹H NMR (600 MHz, DMSO-D₆) δ 9.21 (d, 1H); 8.53 (d, 1H); 8.47 (s,1H); 8.25 (d, 1H); 8.17 (s, 1H); 8.14 (s, 1H); 7.80 (m, 3H); 7.46 (d,1H); 7.40 (d, 1H); 7.34 (m, 3H); 4.71 (s, 2H); 4.27 (d, 2H); 3.88 (s,3H). LRMS (APCI) calculated for C₂₅H₂₁N₅O₄S [M+H]⁺, 488.1; found 488.1.

1. A compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais independently 0 or 1; b is independently 0 or 1; m is independently0, 1, or 2; R¹ is selected from hydrogen, OH, —O—C₁₋₆alkyl, —O-aryl,—O-heterocyclyl, SH, —S—C₁₋₆alkyl, —S-aryl, —S-heterocyclyl, aryl,heterocyclyl and NR⁸R⁹; said alkyl, aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁶; R² and R³ are independently selectedfrom: hydrogen, halo, (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl,(C═O)_(a)O_(b)heterocyclyl, O_(b)C₁-C₆ perfluoroalkyl, or(C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl, heterocyclyl, andcycloalkyl optionally substituted with one, two or three substituentsselected from R⁷; R⁴ and R⁵ are indepedntly selected from hydrogen,C₁₋₆alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, heterocyclyl, OH,—O—C₁₋₆alkyl, (C₁-C₃)perfluoroalkyl, each alkyl, alkenyl, alkynyl,heterocyclyl and aryl optionally substituted with one to threesubstituents, each substituent independently selected from R⁶; R⁶independently is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, (C═O)_(a)O_(b)heterocyclyl, CO₂H, halo, CN, OH,O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a),S(O)₂NR⁸R⁹, OS(═O)R^(a), oxo, CHO, (N═O)R⁸R⁹, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one, two or three substituentsselected from R⁷; R⁷ is independently selected from:(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo,CN, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a),(C₀-C₆)alkylene-CO₂R^(a), C(O)H, (C₀-C₆)alkylene-CO₂H, C(O)N(R^(b))₂,S(O)_(m)R^(a), and S(O)₂NR⁸R⁹; said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, and heterocyclyl is optionally substituted with one, two or threesubstituents selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂; R⁸ and R⁹ are independentlyselected from: H, (C═O)O_(b)C₁-C₁₀ alkyl, (C═O)O_(b)C₃-C₈ cycloalkyl,(C═O)O_(b)aryl, (C═O)O_(b)heterocyclyl, C₁-C₁₀ alkyl, aryl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₈ cycloalkyl, SO₂R^(a), and(C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, andalkynyl is optionally substituted with one, two or three substituentsselected from R⁶, or R⁸ and R⁹ can be taken together with the nitrogento which they are attached to form a monocyclic or bicyclic heterocyclewith 5-7 members in each ring and optionally containing, in addition tothe nitrogen, one or two additional heteroatoms selected from N, O andS, said monocyclic or bicyclic heterocycle optionally substituted withone, two or three substituents selected from R⁷; R^(a) is independentlyselected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl and —(C₁-C₆)alkyleneheterocyclyl; andR^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a). 2.The compound according to claim 1 of the Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais independently 0 or 1; b is independently 0 or 1; m is independently0, 1, or 2; R¹ is selected from hydrogen, OH, —O—C₁₋₆alkyl, —O-aryl,—O-heterocyclyl, SH, —S—C₁₋₆alkyl, —S-aryl, —S-heterocyclyl, aryl,heterocyclyl and NR⁸R⁹; said alkyl, aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁶; R⁴ and R⁵ are indepedntly selected fromhydrogen, C₁₋₁₆alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl,heterocyclyl, OH, —O—C₁₋₆alkyl, (C₁-C₃)perfluoroalkyl, each alkyl,alkenyl, alkynyl, heterocyclyl and aryl optionally substituted with oneto three substituents, each substituent independently selected from R⁶;R⁶ independently is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, (C═O)_(a)O_(b)heterocyclyl, CO₂H, halo,CN, OH, O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a),S(O)₂NR⁸R⁹, OS(═O)R^(a), oxo, CHO, (N═O)R⁸R⁹, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one, two or three substituentsselected from R⁷; R⁷ is independently selected from:(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo,CN, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a),(C₀-C₆)alkylene-CO₂R^(a), C(O)H, (C₀-C₆)alkylene-CO₂H, C(O)N(R^(b))₂,S(O)_(m)R^(a), and S(O)₂NR⁸R⁹; said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, and heterocyclyl is optionally substituted with one, two or threesubstituents selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂; R⁸ and R⁹ are independentlyselected from: H, (C═O)O_(b)C₁-C₁₀ alkyl, (C═O)O_(b)C₃-C₈ cycloalkyl,(C═O)O_(b)aryl, (C═O)O_(b)heterocyclyl, C₁-C₁₀ alkyl, aryl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₈ cycloalkyl, SO₂R^(a), and(C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, andalkynyl is optionally substituted with one, two or three substituentsselected from R⁶, or R⁸ and R⁹ can be taken together with the nitrogento which they are attached to form a monocyclic or bicyclic heterocyclewith 5-7 members in each ring and optionally containing, in addition tothe nitrogen, one or two additional heteroatoms selected from N, O andS, said monocyclic or bicyclic heterocycle optionally substituted withone, two or three substituents selected from R⁷; R^(a) is independentlyselected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl and —(C₁-C₆)alkyleneheterocyclyl; andR^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a). 3.The compound according to claim 2 of the Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais independently 0 or 1; b is independently 0 or 1; m is independently0, 1, or 2; R¹ is selected from OH, —O—C₁₋₁₆alkyl, —O-aryl,—O-heterocyclyl, aryl, heterocyclyl and NR⁸R⁹; said alkyl, aryl andheterocyclyl group optionally substituted with one to five substituents,each substituent independently selected from R⁶; R⁴ is selected fromhydrogen, C₁₋₆alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, heterocyclyl,OH, —O—C₁₋₆alkyl, (C₁-C₃)perfluoroalkyl, each alkyl, alkenyl, alkynyl,heterocyclyl and aryl optionally substituted with one to threesubstituents, each substituent independently selected from R⁶; R⁶independently is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, (C═O)_(a)O_(b)heterocyclyl, CO₂H, halo, CN, OH,O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a),S(O)₂NR⁸R⁹, OS(═O)R^(a), oxo, CHO, (N═O)R⁸R⁹, or (C═O)_(a)O_(b)C₃-C₈cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one, two or three substituentsselected from R⁷; R^(6a) is selected from: C₁-C₁₀ alkyl, aryl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₈ cycloalkyl, C₁-C₆perfluoroalkyl, (C═O)_(b)NR⁸R⁹, S(O)_(m)R^(a) or S(O)₂NR⁸R⁹, said alkyl,aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionallysubstituted with one, two or three substituents selected from R⁷; R⁷ isindependently selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo, CN, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a),(C₀-C₆)alkylene-CO₂R^(a), C(O)H, (C₀-C₆)alkylene-CO₂H, C(O)N(R^(b))₂,S(O)_(m)R^(a), and S(O)₂NR⁸R⁹; said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, and heterocyclyl is optionally substituted with one, two or threesubstituents selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂; R⁸ and R⁹ are independentlyselected from: H, (C═O)O_(b)C₁-C₁₀ alkyl, (C═O)O_(b)C₃-C₈ cycloalkyl,(C═O)O_(b)aryl, (C═O)O_(b)heterocyclyl, C₁-C₁₀ alkyl, aryl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, heterocyclyl, C₃-C₈ cycloalkyl, SO₂R^(a), and(C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, andalkynyl is optionally substituted with one, two or three substituentsselected from R⁶, or R⁸ and R⁹ can be taken together with the nitrogento which they are attached to form a monocyclic or bicyclic heterocyclewith 5-7 members in each ring and optionally containing, in addition tothe nitrogen, one or two additional heteroatoms selected from N, O andS, said monocyclic or bicyclic heterocycle optionally substituted withone, two or three substituents selected from R⁷; R^(a) is independentlyselected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl and —(C₁-C₆)alkyleneheterocyclyl; andR^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a). 4.A compound selected from:N,N-Dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-benzyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(1,4-dioxan-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1-phenylethyl)methanesulfonamide;N-(4-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(2-methylbenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta-1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-methoxybenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(4-methoxybenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(4-fluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(2,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(2-phenylethyl)methanesulfonamide;N-(cyclohexylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-isobutyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-methylbutyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(1-methyl-1H-imidazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-furylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-propylmethanesulfonamide;N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-3-ylmethyl)methane-sulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-methylpyridin-2-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-4-ylmethyl)methanesulfonamide;1,1-Difluoro-N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-Fluoro-N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-3-ylmethanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide;N-[(5-methylpyrazin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(5-methylisoxazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-1,2,4-triazol-5-ylmethyl)methanesulfonamide;N-(1H-benzimidazol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(1H-imidazol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(1H-indol-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-5-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-methylpyridin-4-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(3-thienylmethyl)methanesulfonamide;N-(imidazo[1,2-a]pyridin-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(3-methylisoxazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(imidazo[2,1-b][1,3]thiazol-6-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-phenylisoxazol-5-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(4-methyl-1,3-thiazol-2-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-pyridin-2-ylisoxazol-5-yl)methyl]methanesulfonamide;N-[4-(1H-imidazol-4-yl)benzyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-{[6-(trifluoromethyl)-pyridin-2-yl]methyl}-methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(2-morpholin-4-yl-2-oxoethyl)methanesulfonamide;N˜2˜-({[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl}sulfonyl)glycinamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-{[2-(2-thienyl)-1,3-thiazol-4-yl]methyl}methanesulfonamide;N-[(2-benzyl-1,3-thiazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-pyrazol-3-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,2,3-thiadiazol-4-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridazin-4-ylmethyl)methanesulfonamide;N-[(1-methyl-1H-pyrazol-5-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(1-methyl-1H-pyrazol-4-yl)methyl]1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-ylmethyl)methanesulfonamide;N-[(1-methyl-1H-imidazol-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-oxazol-2-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(3-phenyl-1H-pyrazol-4-yl)methyl]methanesulfonamide;N-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-pyrazol-5-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1H-1,2,3-triazol-4-ylmethyl)methanesulfonamide;N-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrimidin-2-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrimidin-4-ylmethyl)methanesulfonamide;N-[(4,6-dimethylpyrimidin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(3,5-difluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-4-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrazin-2-ylmethyl)methanesulfonamide;N-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-oxazol-4-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyrimidin-5-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(2-phenyl-1,3-thiazol-5-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(6-methylpyridin-2-yl)methyl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1-pyridin-2-ylethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridazin-3-ylmethyl)methanesulfonamide;N-[(5-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(3-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(6-fluoropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(6-bromopyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(5-chloropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(6-chloropyridin-2-yl)methyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-ethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-4-ylmethane-sulfonamide;N-(2-hydroxyethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-pyridin-2-ylmethanesulfonamide;N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)ethanesulfonamide;N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylethanesulfonamide;1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;and1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-[(1-oxidopyridin-2-yl)methyl]methanesulfonamideor a pharmaceutically acceptable salt or stereoisomer thereof.
 5. Apharmaceutical composition that is comprised of a compound in accordancewith claim 1 and a pharmaceutically acceptable carrier.
 6. A method oftreating or preventing cancer in a mammal in need of such treatment thatis comprised of administering to said mammal a therapeutically effectiveamount of a compound of claim
 1. 7. A method of treating cancer orpreventing cancer in accordance with claim 6 wherein the cancer isselected from cancers of the brain, genitourinary tract, lymphaticsystem, stomach, larynx and lung.
 8. A method of treating or preventingcancer in accordance with claim 6 wherein the cancer is selected fromhistiocytic lymphoma, lung adenocarcinoma, small cell lung cancers,pancreatic cancer, liver cancer, gastric cancer, colon cancer, multiplemyeloma, glioblastomas and breast carcinoma.
 9. A method of using thecompound according to claim 1 for the preparation of a medicament usefulin treating or preventing cancer in a mammal in need of such treatment.10. A method of using the compound according to claim 1 for thepreparation of a medicament useful in inhibiting the receptor tyrosinekinase MET in a mammal in need of such treatment.
 11. A method of usingthe compound according to claim 1 for the preparation of a medicamentuseful in preventing or modulating metastasis of cancer in a mammal inneed of such treatment.
 12. The method of using the compound inaccordance with claim 11 wherein the cancer is selected from ovariancancer, childhood hepatocellular carcinoma, metastatic head and necksquamous cell carcinomas, gastric cancer, breast cancer, colorectalcancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreaticcancer, glioblastoma and sarcomas.